Process for making pentaenes



Patented Sept. 9, 1952 PROCESSIFOR MAKING PEN TAENE Joseph Donald S'ur-matis, Pompton Plains, NZJL,

assignor" to Hoflmann-La Roche Inc., N. J.,. a corporation of New Jersey Nutley,

Nil-Drawing; Application Mayl'fi; I951,

SferialNo. 226L735 This invention relatestoan improvement in a synthetic process for makingvitamin A acetate. In particular, it relates to an improved process havingfor its overall object the allyl rearrangement-dehydration of 1-acetoXy SJY dimethyL-S- hydroxy-9-( 2', 6', 6trimethyl cyclohexene--1- yl) -nonatriene-2,4,7 (hereinafter referred toas the tetraene reactant) useful asan intermediate in such a synthesis, e: g., the synthesis described in U. S. Patent 2,451,739, issued October'19, 1948. By the processor the invention, the tetraene reactant is converted to vitamin-A* acetate by treating the former, dissolved in methylenechloride or chloroform, with strong aqueoushydrobromic acid'for a short time'and at a low temperature, and then without delay-subjecting the l-ac'etoxyclohexene-l'-yl) -nonatriene-24,6 formed in the first step to the actionof a dilute aqueous solution of sodium bicarbonate or potassium bicar-- bonate.

In practicing the invention, the only two solvents which have been found suitable are methylene chloride and chloroform; of these, methylene chloride is preferred. The concentration ofthe aqueous hydrobromic acid which can be'usedis critical; acid of about 47.9 per cent to about 'lp9- per cent strength hasbeen found suitable, but a concentration of about 48.0 per cent is preferred.

From about 2.9 to about 3;5 molar proportions of hydrobromic' acid can be'used for-each moi of the tetraene reactant, but i't'is preferred to use about the minus C. upper limit is not overstepped during the bromination reaction. The time during which the bromination is allowed to proceed must be limited to a, period between about 5 and about '7 minutes, but a reaction period of about 6 minutes is preferred. At the end of the reaction period, the bromination reaction is stopped by dropping a large volume of water into the reaction mixture and stirring for a period of from about 5 to about 10 minutes, a period of about '7 minutes being preferred. The preferred volume of water added in order to terminateithe bromination reaction is about 3.0 l. for each mol of tetraene reactant, but quantities within the range from about 2.7 l. to about 3.3 l. have also been used successfully. Stirring is then discontinued and 2 Claims. (Cl. 260-491) the mixtureisallowedto stratify into an aqueous layer and an organic layer, which Stratification requires further periodof-aboutZ minutes. The elapsed" time between the bromination reaction and the dehydrobromination step which follows is thus seen to vary from about? toabout 12 minutes; the preferred elapsed time" being about Qminutes;

The separated organic layer istheri quickly subjected to dehydrobromination by reacting it vvith an aqueous solution of sodium bicarbonate" or potassium bicarbonate; in a concentration of about 5 per cent, sodium bicarbonate being preferred. Slight cooling is desirable, but not mandatory, during this reaction. At least one molar proportion of bicarbonate. must be employed', but excess bicarbonate can. be useduif desired, the amount. of excess-not being critical; a slight molar excess of about 10 per cent is preferred. The dehydrobromination 1 can be effected bystirri'ng the materials togetherlfor about one hour; but in order to insure complete dehydrobromination, it'is preferred to conduct thereaction foraboutthree hours; Attheendof this timByStiIIiIlQiS diS continued andthe mixture'is allowed tostratify.

The organic layer is separated and washed; and

stabilizers are addedthereto: The major part of the-solvent is removed, and crystallinevitamin A acetate is precipitated fromthe residues It will be appreciated from the-foregoing that preferredembodime'nt of theinventioncomprises reactingthe tetraene reactant, dissolved in methylene chloride, with about 3.0 molar proportionsof aqueous hydrobromic acid'having aconcentration of about ldupercent fora period of about 6 minutes'an'd attemperatures increasing from about'minu's25" C. to about minus 15C.; stirring with about, 3.01. of water per'inol of tetra'ene reactant for about 7 minutes; and then quickly separating the organic layer and quickly subjecting it to dehydrobromination-by treating it for about 3 hours witha slight molar; excess of aqueous sodium bicarbonate ina concentration of about 5 per cent.

As compared with prior art processes for effecting the allyl rearrangement-dehydration con version in the synthesis of U. S. Patent 2,451,739, the process of the instant invention is advantageous in that the operating conditions are simpler, the yield is greater, and the quality of the vitamin A-containing product is superior, specifically in that the product is crystalline and stable on storage. An additional advantage of the process of the invention resides in the fact that it can be practiced successfully on a large scale as well as in small scale laboratory experiments.

In setting the above limits to define the area of useful operation according to the instant invention, the intention is to point out as accurately as practicable the range of conditions which give acceptable results. For example, it has been found that aqueous hydrobromic acid of 48.0 per cent strength is preferred, but that acid having a concentration as W as 47.9 per cent or as high as 51.9 per cent'can be employed tov obtain less satisfactory, but still acceptable, results.

til

..tion below 50 C., yielding anorange-colored.

The lower limit is particularly critical:

acid of 47.3 per cent concentration is not acceptable.

a minor or insubstantial degree without departing from the teaching herein, provided that the results obtained are substantially equivalent to those obtained by operation within said stated numerical limits. For example, the use of aqueous hydrobromic acid having a concentration of It will be obvious, however, that the. numerical limits stated may be overstepped to.

47.89 per cent, or a bromination reaction period To a mixture of 40 kg. of 1,6-dihydroxy-3,7- dimethyl-9-(2',6,6-trimethyl cyclohexene 1'- yl) -nonatriene-2,4,7 and 34 l. of pyridine in 120 1. of methylene chloride were added l. of acetyl chloride dissolved in 40 l. ofv methylene chloride, while stirring and at such a rate that the internal temperature did not exceed minus 5 C. While cooling, the stirring was continued for an additional hour, and then the reaction mixture was allowed to stand overnight without stirring or external cooling. were stirred into the reaction mixture, and the organic layer which separated was drawn off, and washed with water and dilute sulfuric acid and then again with water.

To the l-acetoxy-3,7-dimethy1-6hydroxy-9- (2,6,6'etrimethyl-cyclohexene l yl) nonacrime- 2,4,7 (obtained as described above), cooled to minus C., were quickly added 50 l. of hydrobromic' acid, concentration. 48.0 per cent, previously cooled to minus 25 C. The reaction mixture was stirred for 6 minutes, while allowing the temperature to rise to minus 15 C. during this period, and then the reaction was stopped by dropping 400 l. of water into the mixture. After stirring for'7 minutes, the layers were allowed to stratify and the organic layer was quickly separated.

The organic layer was immediately dropped into a well-stirred mixture of 160 l. of water and Tnereupon 80 l. of water 4 kg. of crushed ice. A solution of 20 kg. of sodium bicarbonate in 160 l. of water was added to the reaction mixture within a 10 minute period and stirring was continued for 3 more hours. Then the mixture was allowed to stand overnight. The organic layer was separated and Washed with water. To the washed batch were added 500 cc. 'of pyridine and 425 g. of a-tOCODhQIOI. About per cent of the solvent was removed from the product by flash evaporaviscous syrup. To this were added 50 l. of sub-- stantially anhydrous ethyl alcohol and the mix-- ture was stirred at 0 C. for 12 hours. The re- 'sulting slurry was filtered; light yellow crystal-- line vitamin Aacetate, M. P. 59-60 C., re-

mained on the filter.

I claim:

1. A process of preparing vitamin A acetate which comprises subjecting 1-acetoxy-3,7-di-- methyl-6-hydroxy-9-(25626 trimethyl cyclohexene-l yl) -nonatriene-2,4,7; in solution in a. solvent selected from the group 1 consisting of methylene chloride and chloroforrmto the ac-- tion of from about 2.9 to about 3.5 molar proportions of aqueous hydrobromic acid having a concentration between about 47.9 per cent and about 51.9 per cent, for a period of from about '5. to about 7. minutes and at temperatures between about minus 25 C. and about minus 15 C.;

stirring with from about 2.7 to about 3.3 liters of water per mol of- 1-acetoxy-3,7-dirnethyl-6-' hydroxy-9-(2,6',6'-trimethyl cyclohexene 1'. yl)-nonatriene-2,4,7 for a period of from about 5 to about 10 minutes; and then quickly separating the organic layer and quickly subjecting itv to dehydrobromination by treating it for, a period of from about 1' to about 3 hours with at least one molar proportion of an aqueous solution of an alkali selected from the group consisting of sodium bicarbonate and potassium. bi-

carbonate in a concentration of about 5 per cent.

2. A process of preparing vitamin A'acetate which comprises reacting 1-acetoXy-3,7-dimethyl-6-hydroxy-9- (2',6' ,6 -trimethyl cyclohexene- 1'-yl) -nonatriene-2,4,7, dissolved inmethylenechloride, with about 3.0 molar proportions .of aqueous hydrobromic acid having a concentration of about 48.0 per cent, for a period of about 6 minutes and at temperatures increasing from about minus 25 C. to about minus 15 C.; stirring with about 3.0 liters of water'per. mol of. lhydroxy 9-(2',6,6.-

No references cited. 

1. A PROCESS OF PREPARING VITAMIN A ACETATE WHICH COMPRISES SUBJECTING 1-ACETOXY-3,7-DIMETHYL-6-HYDROXY-9-(2'',6'',6''- TRIMETHYL - CYCLOHEXENE-1''-YL) -NONATRIENC-2,4,7, IN SOLUTION IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF METHYLENE CHLORIDE AND CHLOROFORM,TO THE ACTION OF FROM ABOUT 2.9 TO ABOUT 3.5 MOLAR PROPORTIONS OF AQUEOUS HYDROBROMIC ACID HAVING A CONCENTRATION BETWEEN ABOUT 47.9 PER CENT AND ABOUT 51.9 PER CENT, COR A PERIOD OF FROM ABOUT 5 TO ABOUT 7 MINUTES AND AT TEMPERATURES BETWEEN ABOUT MINUS 25* C. AND ABOUT MINUS 15* C.; STIRRING WITH FROM ABOUT 2.7 TO ABOUT 3.3 LITERS OF WATER PER MOL OF L-ACETOXY-3,7-DEMETHYL-6HYDROXY-9(2'',6'',6''-TRIMETHYL - CYCLOHEXENE - 1'' YL) -HONATRIENE-2,4,7 FOR A PERIOD OF FROM ABOUT 5 TO ABOUT 10 MINUTERS; AND THEN QUICKLY SPEPARATEING THE ORGANIC LAYER AND QUICKLY SUBJECTING IT TO DEHYDROMINATION BY TREATING IT FOR A PERIOD OF FROM ABOUT 1 TO ABOUT 3 HOURS WITH AT LEAST ONE MOLAR PROPORTION OF AN AQUEOUS SOLUTION OF AN ALKALI SELECTED FROM THE GROUP CONSISTING OF SODIUM BICARBONATE AND POTASSIUM BICARBONATE IN A CONCENTRATION OF ABOUT 5 PER CENT. 